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Intravenous Ferric CarboxymaltoseCompared With Oral Iron in the Treatmentof Postpartum AnemiaA Randomized Controlled Trial

David B. Van Wyck,MD , Mark G. Martens,MD , Melvin H. Seid,MD , Jeffrey B. Baker,MD ,and Antoinette Mangione,MD , PharmD

OBJECTIVE: To estimate efficacy of rapid, large-doseintravenous (IV) administration of ferric carboxymaltosecompared with oral iron therapy in anemic postpartum

women.METHODS: In a randomized, controlled trial, we as-signed anemic women (hemoglobin [Hb] less than orequal to 10 g/dL) within 10 days postpartum to receiveeither IV ferric carboxymaltose (less than or equal to1,000mg over 15 minutes, repeated weekly to achieve a totalcalculated replacement dose) or ferrous sulfate (FeSO 4)325 mg orally thrice daily for 6 weeks.RESULTS: One hundred seventy-four patients received350 IV doses of ferric carboxymaltose (mean total dose1,403.1 mg) in 3, 2, or 1 injection (10.9%, 79.3%, or 9.8%of patients, respectively); 178 received FeSO 4. Patients

assigned to IV ferric carboxymaltose compared withthose assigned to oral iron achieved a Hb rise greaterthan or equal to 2.0 g/dL earlier (7.0 compared with 14.0

days, P < .001), were more likely to achieve a Hb risegreater than or equal to 3.0 g/dL at any time (86.3%compared with 60.4%, P < .001), and were more likely to

achieve a Hb greater than 12.0 g/dL (90.5% comparedwith 68.6%, P < .001). A similar proportion of patientsachieved a Hb rise greater than or equal to 2.0 g/dL(96.4% compared with 94.1%, IV compared with oral,P .443). There were no serious adverse drug reactions.CONCLUSION: Large-dose IV ferric carboxymaltose ad-ministration is a new iron agent that is effective for thetreatment of postpartum anemia. When compared withoral ferrous sulfate, IV ferric carboxymaltose is bettertolerated, prompts a more rapid Hb response, and cor-rects anemia more reliably.CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov,www.clinicaltrials.gov, NCT00396292(Obstet Gynecol 2007;110:26778)

LEVEL OF EVIDENCE:I

P ostpartum anemia arises frequently,1 affects low-income and minority women disproportionately,1imposes a substantial disease burden during a criticalperiod of maternalinfant interaction,2 and may giverise to lasting developmental deficits in infants of affected mothers.3 Twenty-one percent of low-incomewomen with a normal hemoglobin in the third trimes-ter of pregnancy present with evidence of anemia at their first postpartum visit.1 As many as 40% of Hispanic women and 48% of non-Hispanic African-American women are afflicted.1 Postpartum anemia adversely affects maternal mood, cognition, and be-havior and disrupts maternalinfant interactions.2 In-fants of mothers who are anemic at 10 weeks postpar-tum show evidence of development delay; moreover,these early deficits in infants are not reversed bysubsequent successful treatment of maternal anemia.3

From the University of Arizona College of Medicine, Tucson, Arizona; University of Oklahoma Health Sciences Center, Tulsa, Oklahoma; Lyndhurst Gynecologic Associates, Winston-Salem, North Carolina; Windmark Women Care Special- ists, Idaho Falls, Idaho; and American Regent, Inc, Norristown, Pennsylvania.

Supported by American Regent, Inc, the human drug division of Luitpold Pharmaceuticals, Shirley, NY.

Corresponding author: David B. Van Wyck, MD, Professor of Medicine and Surgery, Arizona Health Sciences Center, Arizona Center on Aging, 1821 East Elm Street, Tucson, AZ 85719; e-mail: [email protected]. Financial Disclosure

Dr. Van Wyck is a consultant and serves as a speaker for American Regent Inc,a division of Luitpold Pharmaceuticals, Shirley, NY. He is also an investigator for a grant supported by American Regent Inc, and serves on the speakers bureaus for Amgen, Thousand Oaks, CA, and Ortho Biotech, Bridgewater, NJ.Dr. Martens, Dr. Baker, and Dr. Seid have served as research investigators for Luitpold Pharmaceuticals. Dr. Martens and Dr. Seid also serve on the American Regent speakers bureau. Dr. Mangione is an employee of Luitpold Pharmaceu- ticals.

2007 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.ISSN: 0029-7844/07

VOL. 110, NO. 2, PART 1, AUGUST 2007 OBSTETRICS & GYNECOLOGY 267

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Iron deficiency is the most common cause of anemia in the postpartum period.4 Although irontherapy is indicated in the anemic patient, both oraliron agents and currently available intravenous (IV)iron agents pose difficult challenges to effective ironreplacement. Efficacy of oral iron is limited by gas-trointestinal (GI) complaints and patient nonadher-ence,35 whereas treatment with IV iron either risksanaphylaxis when using iron dextran5 or requiresmultiple injections of low doses when using previ-ously available nondextran-containing agents.6,7

Ferric carboxymaltose complex is a nondextran-containing investigational IV iron agent designed tobe administered in large doses by rapid IV injection.The ability to safely inject a single dose as large as1,000 mg in as little as 15 minutes and thereby reducethe need for multiple IV iron infusions renders thisnovel agent a potentially ideal candidate for thetreatment of postpartum anemia. To determinewhether large-dose IV iron administration is an effec-tive iron therapy, we conducted a randomized, con-trolled, noninferiority trial to compare the efficacy of IV ferric carboxymaltose with that of oral ferroussulfate (FeSO4) in the management of patients withearly postpartum anemia.

MATERIALS AND METHODSThis was an open-label, phase 3, randomized, activecontrol, noninferiority, multi-center trial conductedwith institutional review board approval at each of 43sites, including 40 in the United States and three inMexico. In short, we screened patients for potentialeligibility within 5 weeks before expected deliverydate or early after delivery and, within 10 days afterdelivery, enrolled and randomly assigned eligiblepatients to receive either IV ferric carboxymaltose(Injectafer; American Regent, Inc, Shirley, NY) ororal iron therapy, then examined elements of efficacyand safety at intervals for the following 42 days.

We enrolled patients within 10 days after deliverywho demonstrated a hemoglobin (Hb) of 10.0 g/dL orless, were using acceptable contraception or absti-nence, and were able to give informed consent. Thefirst patient was enrolled February 8, 2005, and thelast patient completed, November 11, 2005.

We excluded patients who demonstrated previ-ous nonadherence to prescribed oral iron therapy,history of anemia due to causes other than irondeficiency or blood loss secondary to pregnancy ordelivery, estimated vaginal bleeding more than 100mL in the 24 hours before randomization, activesevere infection, serum transferrin saturation morethan 50%, serum ferritin more than 500 ng/mL,

serum creatinine more than 2.0 mg/dL, serumtransaminases more than 1.5 times upper limit of normal, or evidence of untreated B12 or folate defi-ciency; had received erythropoiesis-stimulating agents (eg, recombinant erythropoietin) within 3months before screening; or showed a history of myelosuppressive therapy, asthma under treatment,hepatitis, human immunodeficiency virus, or hema-tologic disorder other than iron deficiency.

Premature withdrawal was required if an inter-vention for management of anemia was given. Wedefined an anemia intervention as either a red bloodcell transfusion, initiation of erythropoiesis-stimulat-ing agents or iron administration not included in thestudy protocol. Intervention decisions, including thedecision to transfuse, were made by physician discre-tion. Patients who wished to withdraw from the studycould do so at any time without the need to justify thedecision, and investigators could withdraw a patient at any time if withdrawal was felt to be in the best interest of the patient. In the analysis of efficacy andsafety, we included data in each patient up to the timeof withdrawal.

For patients assigned to IV ferric carboxymaltose,we calculated the total iron dose needed to correct anemia and replenish iron stores using the Ganzoniformula,8 modified to include adjustment for baselineiron status:

Prepregnancy weight in kilograms (15baselineHb) 2.4 500.

Fifteen is the target Hb in g/dL, 2.4 is a unitlessconversion constant and 500 is the target iron storesin mg. Baseline Hb reflects the average of two Hbdeterminations (g/dL) obtained 12 hours or moreapart and 18 hours or more postpartum, determinedby local or point-of-care laboratory testing. If trans-ferrin saturation was more than 20%and ferritin morethan 50 ng/mL, 500 mg was subtracted.

Within 32 hours after determining baseline Hb,we initiated administration of the total calculateddose. The maximal dose administered in a single daywas 15 mg/kg, not to exceed 1,000 mg. If the totalcalculated dose exceeded 1,000 mg, subsequent doseswere administered weekly until the total dose wasreceived, up to a maximal total dose of 2,500 mg.Intravenous iron was supplied as ferric carboxymal-tose complex (American Regent, Inc., Shirley, NY),500 mg elemental iron in 10 mL water. We adjustedinjection volume and rate of administration by doserange as follows: 200 mg or less undiluted over 12minutes; 300400 mg in 100 mL normal saline over6 minutes; 5001,000 mg in 250 mL normal salineover 15 minutes.

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For patients assigned to oral ferrous sulfate, wedispensed ferrous sulfate as 325-mg tablets (65 mg elemental iron) with instructions to take one tablet bymouth three times daily with 8 ounces of tap water, 1hour before meals from day 0 until day 42. Wedispensed tablets in blister packs of 25 tablets each,including one blister pack on days 0 and 7, and 2blister packs on days 14 and 28. Used blister packswere returned to assess adherence to prescribedtherapy.

Our hypothesis was that IV iron administrationusing ferric carboxymaltose complex is at least aseffective as administration of oral iron in the correc-tion of postpartum anemia. We chose ferrous sulfateas the comparator because administration of a ferroussalt is the accepted standard of care for treatment of postpartum anemia.

To examine efficacy, we defined the primaryefficacy endpoint as the proportion of patients with a

Hb increase 2 g/dL or more after treatment. Second-ary measures of efficacy included the proportion of patients attaining a hemoglobin more than 12.0 g/dL(correction of anemia); the proportion achieving anincrease in hemoglobin 3 g/dL or more; time toachieve the primary outcome; peak Hb increase frombaseline; time to peak Hb increase; maximal increasein ferritin, transferrin saturation, reticulocyte count, orreticulocyte hemoglobin content; number of patientsrequiring intervention; time to intervention; propor-tion of patients with a Hb increase 2 g/dL or moreand ferritin increase 160 ng/mL or more; and propor-

tion of patients with improved quality of life. We useda central laboratory for all analyses of outcomes andlocal laboratories and point-of-care testing to deter-mine Hb values needed to qualify for randomizationor to calculate total iron dose.

We assessed health-related quality of life using normalized data from the Medical Outcomes StudyShort Form 36 (SF-36) instrument, version 29 and theFatigue Linear Analog Scale Assessment.10 To nor-malize results, we first transformed item scores so that large values represented positive outcomes; trans-formed item scores were then summed to obtaindimension scores; and, finally, dimension scores weretransformed to a 0100 scale (worst-best) to obtaincomponent scores. We defined a change from base-line that exceeded 0.5 standard deviation of thebaseline mean as a minimally important difference.11The reference population for reporting normativeSF-36 results for Physical Component Summary andMental Component Summary scales were those ob-tained from a population survey of randomly se-

lected, community-dwelling, 25- to 34-year-old U.S.females.9

To assess safety, we monitored blood pressureand recorded adverse events in all patients before,during, and after administration of IV iron and askedall patients to report any untoward medical event at its onset. We recorded adverse events from the day of consent through the completion of the study (day 42)or 30 days after the last dose of study drug, whicheverwas later. Investigators provided the onset and reso-lution date, severity, relationship to study drug, actiontaken, and outcome of the adverse event. We did not consider worsening anemia or iron deficiency to beadverse events, because these developments becamestudy endpoints if an anemia intervention was re-quired, as defined above.

To estimate sample size, we assumed that 80% of patients in each treatment group would be compliant with dosing and achieve the primary endpoint. Basedon this assumption, a sample size of 160 patients pertreatment group provided 85% power to achieve a 97.5% two-tailed confidence bound 15% or more forthe treatment difference (IV iron minus oral iron) insuccess rate. The study was not powered for safetyconsiderations.

Patients who had met all of the inclusion andexclusion criteria were stratified by Hb levels (9.110.0 g/dL, 8.19.0 g/dL, 8.0 g/dL or less) and require-ment for cesarean delivery and screening iron indices(transferrin saturation more than 20% and ferritinmore than 50 ng/mL, transferrin saturation 20% orless or ferritin 50 ng/mL or less). Stratified randomtreatment assignments were prepared using comput-erized random number generation, blocked random-ization, and an interactive voice response system.

In the analysis of the primary efficacy endpoint,noninferiority was demonstrated if the one-tailed97.5% confidence bound for the treatment differencein success rate (IV iron results minus oral iron results)was 15% or more. If the bound exceeded zero,superiority of IV iron to oral iron was demonstrated.The confidence bound was based on the normalapproximation to the binomial distribution without stratification.

We determined the effect of baseline characteris-tics on the primary efficacy endpoint by logisticregression. Baseline covariates included Hb, ferritin,transferrin saturation, age, race, method of delivery(vaginal, cesarean delivery), estimated blood lossfrom delivery, and number of neonates delivered.

In the analysis of secondary efficacy endpoints,treatment differences in proportions were assessedwith Fisher exact test. We estimated time-to-event

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curves using the Kaplan-Meier method and examinedfor treatment group differences using the log rank test.We used repeated measures analysis to comparechanges from baseline between groups.

RESULTSThree hundred sixty-one (361) patients were ran-domly allocated at 43 centers to receive IV iron (asferric carboxymaltose; 182 patients) or oral iron (fer-rous sulfate; 179 patients). Of these 361 patients, eight assigned to IV ferric carboxymaltose and one as-signed to oral iron discontinued from the study beforedosing and were excluded from the evaluated popu-lation. The safety population included 352 patientswho received at least one dose of treatment medica-tion: 174 patients in the IV ferric carboxymaltosegroup and 178 in the oral iron group (Fig. 1). Theintent-to-treat population, which formed the basis forefficacy analysis, included all safety patients except those who lacked at least one Hb determination afterbaseline (five IV ferric carboxymaltose patients;seven oral iron patients) and those who on reviewlacked Hb less than 11 g/dL at baseline (one IV ferriccarboxymaltose patient, two oral iron patients). Ac-cordingly, the intent-to-treat population consisted of 168 IV ferric carboxymaltose patients and 169 oraliron patients.

Of the safety population, 165 (94.8%) of the 174

patients in the IV ferric carboxymaltose group and162 (91.0%) of the 178 patients in the oral iron groupcompleted the study. The nine patients in the IVferric carboxymaltose group who did not completethe study included four due to patient request, twodue to adverse events, two lost to follow-up, and onereceived intervention (nonstudy iron).

The 16 patients in the oral iron group who did not complete the study included seven lost to follow-up,four discontinued due to adverse events, three foundafter randomization not to have met the selection orstudy compliance criteria and two discontinued dueto patient request.

Among patients in the intent-to-treat population,there were no significant differences at baseline be-tween patients in the IV ferric carboxymaltose groupand those in the oral iron group in demographicdescriptors, iron status, or severity of anemia (Table1). Adherence to prescribed therapy was greateramong patients in the IV ferric carboxymaltose groupcompared with those in the oral iron group (meanpercent adherence 98.0% compared with 83.9%; 95%CI: 95.8100.2 compared with 80.187.7). Five pa-tients assigned to IV ferric carboxymaltose and 19assigned to oral iron received less than 67% of theprescribed dose.

In the IV ferric carboxymaltose group comparedwith the oral iron group, there was no between-group

Fig. 1. Disposition of study participants by treatment assignment.Van Wyck. IV Ferric Carboxymaltose for Postpartum Anemia. Obstet Gynecol 2007.

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difference in the proportion of patients who achievedthe primary endpoint, a rise in Hb 2.0 g/dL or morewithin 42 days after baseline (96.4% compared with94.1%, 95% CI 2.19 to 6.88,P .443, Fig. 2). The CIfor the differences in success rates demonstrated thenoninferiority of ferric carboxymaltose relative to oraliron. However, the median time to achieve the pri-mary endpoint (Hb rise 2.0 g/dL or more) was shorterin patients assigned to IV ferric carboxymaltose com-pared with oral iron treatment (7.0 compared with14.0 days, P .001). The proportion of patients whoachieved a rise in Hb 3.0 g/dL or more was greater at each treatment interval after day 7 (Fig. 2), and theproportion of patients who experienced correction of anemia (achieving Hb mor than 12.0 g/dL) washigher both overall (90.5% compared with 68.6%,P .001) and at each treatment interval in the IV ferriccarboxymaltose group. Among patients assigned tooral iron, but not among those assigned to IV ferriccarboxymaltose, the percentage of patients achieving Hb 12 g/dL or more decreased as the baseline Hbdecreased. Between-group differences in efficacywere therefore greatest in those patients with the most severe anemia (Fig. 3). Moreover, among patientsassigned to IV ferric carboxymaltose compared withthose assigned to oral iron, the overall erythropoieticresponse (Hb, hematocrit [Hct], reticulocytes, meancorpuscular volume, mean corpuscular hemoglobinand reticulocyte hemoglobin content) was more ro-bust at most treatment intervals (Fig. 4).

Serum ferritin increased promptly in the IV ferriccarboxymaltose treatment group but failed to increasein the oral iron group. Differences between groups

were significant at each study interval (Fig. 5). trans-ferrin saturation increased significantly at every inter-val in both groups, related to a rise in serum iron andfall in total iron-binding capacity (TIBC); however,IV irontreated patients showed higher transferrinsaturation at each interval after the first week, associ-ated with a more pronounced rise in serum iron andfall in TIBC (Fig. 5).

The completion rates for the health-related quality-of-life assessments in the IV ferric carboxymaltose andoral iron groups were 94.8% and 91.0%, respectively. Inboth treatment groups, baseline scores were lower thanthe expected normal values for the SF-36 physicalcomponent summary but above normal values for themental component summary (Fig. 6). Patients assignedto IV ferric carboxymaltose or oral iron experiencedsimilar increases in SF-36 scores and decreases in Fa-tigue Linear Analog Scale Assessment scores. Between-group differences were not significant at any study

interval. The within-group change from baseline to day42 met or exceeded criteria for minimum important difference for every health-related quality-of-life scaleexcept SF-36 Role-Emotional.

The mean cumulative per patient dose of IVferric carboxymaltose administered was 1,403.1 mg (95% CI of the mean 1,344.61,461.6) and the meancumulative dose of oral iron was 6,764.0 mg (6,383.07,145.0). There were 350 total injections of IV ferriccarboxymaltose administered: 17 patients (9.8%) re-ceived only one injection, 138 (79.3%) received twoinjections, and 19 (10.9%) received three injections.Of the 174 patients assigned to receive IV ferric

Fig. 2. Percentage of study participants achieving anemia endpoints according to treatment assignment (IV ferriccarboxymaltose given on days 0, 7, or 14 or oral ferrous sulfate thrice daily on days 042). A. Primary study endpoint, Hbincrease 2 g/dL or more. B. Secondary endpoint, Hb increase 3.0 g/dL or more. C. Secondary endpoint, achieved Hb 12.0g/dL or more. Between-group comparisons: * P .05; **P .01; ***P .001. Solid line with circle, intravenous ferriccarboxymaltose; solid line with triangle, oral ferrous sulfate.Van Wyck. IV Ferric Carboxymaltose for Postpartum Anemia. Obstet Gynecol 2007.


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Fig. 3. Relationship between severity of anemia at baseline and probability of achieving a Hb 12.0 g/dL or more after irontherapy. Intravenous ferric carboxymaltose was given on days 0, 7, or 14 or oral ferrous sulfate thrice daily on days 042.Between-group comparisons: * P .05; **P .01.Van Wyck. IV Ferric Carboxymaltose for Postpartum Anemia. Obstet Gynecol 2007.

Fig. 4. Change in markers of hematologic response from baseline according to treatment assignment. A. Hematocrit (HCT).B. Mean corpuscular volume (MCV). C. Hemoglobin (Hb). D. Mean corpuscular hemoglobin (MCH). E. Reticulocytes. F.Content of hemoglobin in reticulocytes. Intravenous ferric carboxymaltose was given on days 0, 7, or 14 or oral ferroussulfate thrice daily on days 042. Solid line with circle, intravenous ferric carboxymaltose; solid line with triangle, oralferrous sulfate. Between-group comparisons: * P .05; **P .01; ***P .001.Van Wyck. IV Ferric Carboxymaltose for Postpartum Anemia. Obstet Gynecol 2007.

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carboxymaltose, 151 (86.8%) received total doses that exceeded 1,000 mg.

No serious drug-related adverse events occurredin either treatment group. Patients assigned to oraliron therapy were more likely to report gastrointesti-nal complaints, particularly constipation and nausea,whereas those assigned to IV ferric carboxymaltosewere more likely to experience skin disorders, prin-cipally mild pruritus and rash that usually occurredduring or shortly after IV ferric carboxymaltose infu-sion and resolved within 515 minutes (Table 2).Eight patients received a second injection of IV ferriccarboxymaltose after experiencing an episode of pru-ritus, rash, or both with the first injection; of these,three experienced recurrent findings, again mild andtransient.

One patient assigned to oral iron developeddepression and was discontinued from the trial.One patient assigned to IV ferric carboxymaltose(baseline Hb 7.9 g/dL) died 13 days after vaginaldelivery, 7 days after IV iron injection, and autopsyconfirmed peripartum cardiomyopathy. Neitherevent was considered by the investigator to bedrug-related. There were 46 infections reported, 24in the IV ferric carboxymaltose treatment group,and 22 in the oral iron treatment group (13.8%compared with 12.4%,P .753). None were thought

to be related to study drug. No episodes of phlebitiswere reported in the IV ferric carboxymaltosetreatment group.

Discontinuation of study drug due to drug-relatedadverse effects occurred in one patient assigned to theIV ferric carboxymaltose treatment arm and in fivepatients assigned to the oral iron arm. The patient assigned to IV ferric carboxymaltose experienced a pruritic rash described as probably related to studydrug 3 days after receiving a 600 mg dose. Of the fivepatients in the oral iron treatment group, four discon-tinued due to gastrointestinal complaints (nausea,vomiting, or diarrhea) and one due to elevated serumtransaminase.

We observed several statistically significant changes in nonhematologic clinical chemistry resultsduring the course of the trial. Most changes showedno between-group differences, suggesting that theywere related to the natural history of the postpartumcondition (Tables 13). We saw a transient fall, how-ever, in serum phosphate among patients in the IVferric carboxymaltose treatment group which reachednadir at study day 14 (delta phosphate from baseline,1.1 0.77 compared with 0.0 0.73 mg/dL, IV ferriccarboxymaltose compared with oral iron, respec-tively, P .001) and returned to baseline by day 42.Although mean serum phosphate was unchanged in

Fig. 5. Change in serum markers of iron status from baseline according to treatment assignment. A. Ferritin. B. Iron. C.Transferrin saturation (TSAT). D. Total iron binding capacity (TIBC). Intravenous ferric carboxymaltose was given on days0, 7, or 14 or oral ferrous sulfate thrice daily on days 042. Solid line with circle, intravenous ferric carboxymaltose; solid line with triangle, oral ferrous sulfate. Between-group comparisons: * P .05; ***P .001.Van Wyck. IV Ferric Carboxymaltose for Postpartum Anemia. Obstet Gynecol 2007.


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the oral iron treatment group, in both treatment groups there was a highly significant relationshipbetween baseline serum phosphate level and themaximal decrease in serum phosphate from baseline(IV ferric carboxymaltose Pearsons r 0.22,P .004; oral iron Pearsons r 0.69, P .001). Theserum phosphate decreases after oral and IV ferriccarboxymaltose therapy were highest in those withhighest baseline serum phosphate. Serum calciumrose in both groups throughout the study, but theincrease was slightly less in the IV ferric carboxymal-tose group compared with the oral iron group at day7 and 14 (delta calcium from baseline, 0.4 0.5 com-pared with 0.6 0.5 mg/dL, day 14, P .001). Serumalbumin increased in both groups (peak increase,mean standard deviation: 1.4 0.4 compared with1.3 0.4 g/dL, IV iron compared with oral iron,P .189).

DISCUSSIONWe undertook the current study to compare twotreatments, IV ferric carboxymaltose and oral ferroussulfate, for management of a common disorder, post-partum anemia. Our results provide new informationnot previously available on the efficacy of IV ironcompared with oral iron therapy in managing post-partum anemia, the effect and reversibility of anemia on quality of life in postpartum patients, the rate of patient adherence to IV compared with oral irontreatment, the potential adverse effects and nonhema-tologic clinical chemistry changes after therapeuticiron intervention, and the use of ferric carboxymal-tose complex for rapid IV administration of large irondoses.

The prevalence and potential adverse effect of postpartum anemia on women and infants, coupledwith substantial drawbacks to use of currently avail-

Fig. 6. Health-related quality of life in patients after iron treatment. Results are shown as mean scores of the MedicalOutcomes Study Short Form 36 Health Survey (SF-36), including eight components ( AD and FI) and two summarycomponent scores ( E, J) and as mean scores of the 10-cm Fatigue Linear Analogue Scale ( K). Increases in SF-36 scores anddecreases in Linear Analog Scale Assessment scores reflect improvement. Reference values for SF-36 summary componentscores (E, J) are given for the general U.S. population of 2534-year-old females. 9 Solid line with circle, IV ferriccarboxymaltose; dotted line with circle, oral ferrous sulfate; dashed line, reference.Van Wyck. IV Ferric Carboxymaltose for Postpartum Anemia. Obstet Gynecol 2007.

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able iron agents, render an IV iron agent that can besafely administered in one to three large doses a useful therapeutic asset. Clearly, both oral iron agentsand currently available IV iron agents pose difficult challenges to effective management in this patient population. Oral iron agents are inexpensive andmodestly effective. Anemic postpartum patients re-ceiving oral iron, compared with their counterpartsreceiving placebo12 or no treatment,13 experience a more rapid increase in Hb, a more rapid correction of anemia, and a slight improvement in iron stores.However, GI complaints afflict up to 20% of patientstaking ferrous iron salts,14,15 as many as 30% of unselected patients may be totally nonadherent toprescribed therapy,16 and efficacy hinges, of course,on prolonged, successful adherence to a twice orthrice-daily pill-taking regimen.17

True to previous experience, we found significant

drawbacks to oral iron therapy. Although Hb and Hct increased in patients assigned to oral iron, some of this increase can be ascribed to the expected decreasein plasma volume that follows delivery.13,18 We foundthat patients in the oral iron treatment group showedlittle discernable evidence of improved adequacy of iron supply for erythropoiesis as measured by trans-ferrin saturation, reticulocyte hemoglobin content,mean corpuscular volume, mean corpuscular hemo-globin, or reticulocyte count or improved iron storesas measured by serum ferritin. Previous trials haveshown that postpartum patients treated with oral iron,when compared with those receiving placebo only,correct anemia earlier,13 achieve higher levels of Hb,ferritin, transferrin saturation, and stainable bonemarrow iron and achieve lower levels of TIBC,soluble transferrin receptor (sTfR), and percent hypo-chromic red cells.12,18 Although peak Hb response

Table 1. Baseline Demographics in the Intent-to-Treat Population

Baseline CharacteristicIV Ferric Carboxymaltose

(n 168)Oral Ferrous Sulfate

(n 169) P

Age (y) 26.9 ( 6.4) 26.1 ( 6.0) .180Weight (kg) 76.4 ( 19.1) 81.0 ( 19.7) .035Race .231

White 88 ( 52.4) 77 ( 45.6)Hispanic 44 ( 26.2) 51 ( 30.2)

African American 31 ( 18.5) 37 ( 21.9)Other 5 ( 3.0) 4 ( 2.4)Hb (g/dL) 9.0 ( 0.9) 9.0 ( 1.0) .864Hb category (g/dL, %)* .857

9.110.0 81 (48.2) 86 (50.9)8.19.1 55 (32.7) 54 (32.0)8.0 or less 32 (19.0) 29 (17.2)

TSAT (%) 10.6 ( 9.0) 9.8 ( 4.3) .311Ferritin (ng/mL) 26.1 ( 36.6) 23.7 ( 24.0) .489Previous treatment with oral iron 139 ( 82.8) 145 ( 86) .458Intolerance to previous oral iron agent (%) 6 (3.6) 4 (2.4) .542IV, intravenous; Hb, hemoglobin; TSAT, transferrin saturation.Data in parentheses are standard deviation unless otherwise noted.* At randomization.

Table 2. Adverse Reactions by More Than 2% of Patients (Safety Population) in Either Treatment Group,by Classification, Considered to Be Drug-Related by Investigator

Adverse Event ClassificationIV Ferric Carboxymaltose

(n 174)Oral Ferrous Sulfate

(n 178) P All GI disorders 11 (6.3) 43 (24.2) .001Constipation 6 (3.4) 20 (11.2) .007Diarrhea 0 (0.0) 7 (3.9) .015Nausea 2 (1.1) 13 (7.3) .006Pruritus, rash, or both 9 (5.2) 4 (2.2) .164Serum transaminase elevation 1 (0.6) 5 (2.8) .215Headache 10 (5.7) 5 (2.8) .196IV, intravenous; GI, gastrointestinal.Data are n (%).


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with or without treatment is seen within 4 weekspostpartum, any continued improvement in iron sta-tus thereafter requires continued oral iron administra-tion.12 Taken together with these reports, our findingsare in keeping with the conclusion that postpartumpatients receiving oral iron therapy for 6 weeks showlittle evidence of improved iron stores, limited im-provement in adequacy of iron supply for erythropoi-esis, and a modest boost to Hb and Hct.

The conclusion that oral iron efficacy is limitedmay be explained in part by frequent GI complaintsand high rates of nonadherence with prescribed ther-apy. Nonadherence to oral iron prescription is di-rectly related to severity of GI symptoms,14 andefficacy is known to diminish as nonadherence in-creases.14,16 We found that both GI complaints andnonadherence were higher among patients assignedto oral iron therapy than in those assigned to IV ferriccarboxymaltose. Clinicians are likely to encounterhigher rates of nonadherence than we observed,because study patients were selected for willingness toparticipate and absence of previous intolerance, weregiven iron tablets rather than prescriptions, and re-ceived regular encouragement from study personnel.

By comparison, large-dose administration of fer-ric carboxymaltose showed robust evidence of effi-cacy, tolerability, and safety. We confirmed that IVferric carboxymaltose is at least as effective as oraliron in achieving the primary endpoint, a Hb increase

2.0 g/dL or more. Importantly, more than 90% of patients received the calculated iron replacement inonly one or two ferric carboxymaltose doses, noserious adverse reactions were observed, and onlyone patient discontinued treatment due to drug-re-lated effects (rash and pruritus).

In multi-center clinical trials to date, a total of 4,903 doses of ferric carboxymaltose have been givento 2,065 patients without serious drug related adversedrug events (data on file, Luitpold Pharmaceuticals,Norristown, PA). The mean maximal single dose inthese trials was 800 mg ( 295 standard deviation). Bycontrast, to avoid hypotension and other dose-relatedadverse drug effects, administration of currently avail-able IV iron agents is limited to 100 mg of irondextran over 2 minutes, 125 mg of ferric gluconateover 10 minutes, or 200 mg of iron sucrose over 25minutes. Higher doses of iron sucrose are U.S. Foodand Drug Administrationapproved, but only forslow IV administration (up to 400 mg over 2.5 hours)and only for specific indications in chronic kidneydisease. In short, ferric carboxymaltose complexseems to afford the efficacy of IV iron administrationwithout the inconvenience of multiple small-doseinjections, the long infusion times and risk of adversedrug effects associated with higher IV iron doses, andthe inconvenience, adverse GI effects, and risk of nonadherence associated with thrice-daily oral irontherapy.

Table 3. Baseline Clinical Laboratory Values and Change From Baseline in Postpartum Patients Assignedto Intravenous Iron or Oral Iron Treatment (Safety Population)

IV Ferric Carboxymaltose Oral Ferrous SulfateBetween-

GroupComparisonof Changes P Analyte Baseline

Change atDay 42

Within-GroupSignificanceof Change P Baseline

Change atDay 42

Within-GroupSignificanceof Change P

Albumin (g/dL) 2.9 1.3 .001 2.8 1.3 .001 .331

C-reactiveprotein (mg/dL) 4.5 4.0 .001 4.9 4.4 .001 .471

ALT (units/L) 24.7 4.8 .041 23.4 3.7 .066 .726AST (units/L) 27.0 3.4 .041 25.4 1.2 .361 .321Alkaline

phosphatase(units/L) 129.0 25.9 .001 128.4 31.0 .001 .178GGT (units/L) 14.7 5.3 .079 16.0 0.4 .805 .096LDH (units/L) 279.6 102.8 .001 281.4 98.7 .001 .656Creatinine

(mg/dL) 0.6 0.1 .001 0.7 0.1 .001 .949Urea nitrogen

(mg/dL) 11.1 1.5 .001 10.3 1.8 .001 .419IV, intravenous; ALT; alanine transaminase; AST, aspartate transaminase; GGT, -glutamyltransferase; LDH,L -lactate dehydrogenase.

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Health-related quality of life and transfusion re-quirements constitute the direct patient outcomesmost likely to be affected by anemia and reversiblewith iron therapy. In a randomized control trial inpatients with moderate postpartum anemia (Hb morethan 10.0 g/dL), quality-of-life improvement, in par-allel with anemia correction, occurred earlier among patients treated with oral iron than among untreatedpatients.13 In the current trial, we confirmed that untreated women with postpartum anemia suffer sub-stantial health-related quality-of-life morbidity, evi-dencing particularly poor scores for fatigue, physicalfunction and vitality. Our results also show that earlyintervention with effective iron therapy, regardless of the route of administration, dramatically improveshealth-related quality of life in women with postpar-tum anemia. Generalization of the health-relatedquality-of-life results from the current trial to clinicalpractice is, however, limited by the low numbers of study patients with severe anemia (less than 20% of patients in either treatment group with Hb less than8.0 g/dL), use of measures to maximize oral ironadherence that are not commonly available in prac-tice (provision of tablets, early and frequent follow-up,pill-counting, counseling for nonadherence), and thelack of information on maternalinfant behavior andinfant development. Finally, no patient in either treat-ment arm received red blood cell transfusion, consis-tent with previous findings that transfusion therapyafter vaginal or caesarian delivery is uncommon.19

We serially examined a number of routine clini-cal laboratory chemistries in addition to markers of hematologic and iron status response. For most ana-lytes, including serum albumin, C-reactive protein,hepatic enzymes, creatinine, and urea nitrogen (Table3), the changes we observed followed the expectedpostpartum course.20 However, we also saw a consis-tent, asymptomatic, and transient decrease in serumphosphate among patients assigned to IV iron ther-apy. Significant hypophosphatemia has been reportedearly after initiation of hemolytic anemia,21 during recovery from aplastic crisis associated with heredi-tary spherocytosis,22 and during reconstitution of he-matopoiesis after allogeneic peripheral blood stemcell transplantation,23 suggesting that cellular uptakeof phosphate during accelerated erythropoiesis maybe sufficient to acutely lower extracellular phosphateconcentration. Alternatively, a fall in serum phos-phate may reflect correction of intracellular phos-phate depletion, a condition described after inductionof iron deficiency in experimental animals.24,25 Wefound that the degree of phosphate decrease wasrelated to baseline phosphate level: the higher the

baseline serum phosphate, the greater the observedmaximal decrease after iron therapy. Because weobserved a similar relationship in both the IV andoral treatment arms, the greater degree of phosphatefall in the IV irontreated patients likely reflectsgreater efficacy of IV iron in either stimulating eryth-ropoiesis, replenishing iron stores, or both and that the mechanism of phosphate lowering is intrinsic toiron therapy.

To apply findings of the current study to treat-ment of unselected patients with postpartum anemia,several specific limitations of our study and those of others should be considered. First, our results show-ing superior efficacy of IV iron over oral iron are not consistent with the negative findings of the singleprevious RCT comparing oral iron, IV iron, and IViron plus epoetin alfa.6 However, treatment groups inthat trial were small (n 20 each), the observationperiod was short (14 days), and the total dose of ironsucrose was limited to 800 mg (200 mg IV per day ondays 14). By contrast, our study included resultsfrom more than 160 patients in each treatment armfollowed for 42 days and given iron doses calculatedto both correct anemia and replenish iron stores.Second, our information on the efficacy of oral iron islimited to 42 days of administration. Continued ad-ministration of oral iron therapy up to 12 weekspostpartum has, however, been previously examinedin a small trial.12 Beyond 4 weeks, continued oral irontherapy is associated with no further increase in Hb orferritin, a slight increase in transferrin saturation, anda progressive decline in percent hypochromic redcells and sTfR.12 Thus, prolongation of oral irontherapy beyond 28 days may increase adequacy of iron for erythropoiesis (as indicated by changes intransferrin saturation, percent hypochromic red cellsand sTfR) but does not seem to afford a furtherincrease in Hb or iron stores (as reflected by serumferritin). Finally, longer trials will be needed to con-firm whether the higher iron stores achieved in IVirontreated patients signify a persistent treatment benefit in women with ongoing menses or subsequent

pregnancy.These limitations notwithstanding, our results are

important for clinicians because they shed new light on the severity of quality-of-life deficits associatedwith postpartum anemia, confirm that effective irontherapy corrects both the anemia and the quality-of-life deficits, and describe evidence for a new thera-peutic option, an iron agent that can reduce the needfor multiple IV iron infusions.


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